Thomas E Hall

University of Queensland, Brisbane, Queensland, Australia

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Publications (29)166.71 Total impact

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    ABSTRACT: Microglia are specialized phagocytes in the vertebrate central nervous system (CNS). As the resident immune cells of the CNS they play an important role in the removal of dying neurons during both development and in several neuronal pathologies. Microglia have been shown to prevent the diffusion of damaging degradation products of dying neurons by engulfment and ingestion. Here we describe a live imaging approach that uses UV laser ablation to selectively stress and kill spinal neurons and visualize the clearance of neuronal remnants by microglia in the zebrafish spinal cord. In vivo imaging confirmed the motile nature of microglia within the uninjured spinal cord. However, selective neuronal ablation triggered rapid activation of microglia, leading to phagocytic uptake of neuronal debris by microglia within 20-30 min. This process of microglial engulfment is highly dynamic, involving the extension of processes toward the lesion site and consequently the ingestion of the dying neuron. 3D rendering analysis of time-lapse recordings revealed the formation of phagosome-like structures in the activated microglia located at the site of neuronal ablation. This real-time representation of microglial phagocytosis in the living zebrafish spinal cord provides novel opportunities to study the mechanisms of microglia-mediated neuronal clearance.
    Frontiers in Cellular Neuroscience 09/2015; 9:321. DOI:10.3389/fncel.2015.00321 · 4.29 Impact Factor
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    ABSTRACT: Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle α-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z-disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1(D286G) mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness.
    Acta Neuropathologica 05/2015; 130(3). DOI:10.1007/s00401-015-1430-3 · 10.76 Impact Factor
  • Joachim Berger · Thomas E Hall · Peter D Currie
    Zebrafish 01/2015; 12(1). DOI:10.1089/zeb.2014.1065 · 1.95 Impact Factor
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    ABSTRACT: Nemaline myopathy is an inherited muscle disease that is mainly diagnosed by the presence of nemaline rods in muscle biopsies. Of the 9 genes associated with the disease, 5 encode for components of striated muscle sarcomeres. In a genetic zebrafish screen the mutant träge (trg) was isolated based on its reduction in muscle birefringence, indicating muscle damage. Myofibres in trg appeared disorganized and showed inhomogeneous cytoplasmic eosin staining alongside malformed nuclei. Linkage analysis of träge combined with sequencing identified a nonsense mutation in tropomodulin4 (tmod4), a regulator of thin filament length and stability. Accordingly, while actin monomers polymerise to form thin filaments in skeletal muscle of tmod4(trg) mutants, thin filaments often appeared dispersed throughout myofibres. Organised myofibrils with the typical striation rarely assemble, leading to severe muscle weakness, impaired locomotion, and early death. Myofibril of tmod4(trg) mutants often featured thin filaments of various lengths, widened Z-disks, undefined H-zones, and electron-dense aggregations of various shapes and sizes. Importantly, Gomori trichrome staining and the lattice pattern of the detected cytoplasmic rods together with the reactivity of rods with phalloidin and an antibody against actinin is reminiscent of nemaline rods found in nemaline myopathy, suggesting that misregulation of thin filament length causes cytoplasmic rod formation in tmod4(trg) mutants. While tropomodulin4 has not been associated with myopathy, the presented results make TMOD4 a novel candidate for unresolved nemaline myopathies and suggest the tmod4(trg) mutant as a valuable tool to study human muscle disorders.
    Disease Models and Mechanisms 10/2014; 7(12). DOI:10.1242/dmm.017376 · 4.97 Impact Factor
  • 19th International Congress of the World-Muscle-Society; 10/2014
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    ABSTRACT: Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs.
    Nature 08/2014; 512(7514). DOI:10.1038/nature13678 · 41.46 Impact Factor
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    ABSTRACT: FUS mutations can occur in familial amyotrophic lateral sclerosis (fALS), a neurodegenerative disease with cytoplasmic FUS inclusion bodies in motor neurons. To investigate FUS pathology, we generated transgenic zebrafish expressing GFP-tagged wild-type or fALS (R521C) human FUS. Cell cultures were made from these zebrafish and the subcellular localization of human FUS and the generation of stress granule (SG) inclusions examined in different cell types, including differentiated motor neurons. We demonstrate that mutant FUS is mislocalized from the nucleus to the cytosol to a similar extent in motor neurons and all other cell types. Both wild-type and R521C FUS localized to SGs in zebrafish cells, demonstrating an intrinsic ability of human FUS to accumulate in SGs irrespective of the presence of disease-associated mutations or specific cell type. However, elevation in relative cytosolic to nuclear FUS by the R521C mutation led to a significant increase in SG assembly and persistence within a sub population of vulnerable cells, although these cells were not selectively motor neurons.
    PLoS ONE 06/2014; 9(6):e90572. DOI:10.1371/journal.pone.0090572 · 3.23 Impact Factor
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    ABSTRACT: One of the central questions of developmental biology is how cells of equivalent potential-an equivalence group-come to adopt specific cellular fates. In this study we have used a combination of live imaging, single cell lineage analyses, and perturbation of specific signaling pathways to dissect the specification of the adaxial cells of the zebrafish embryo. We show that the adaxial cells are myogenic precursors that form a cell fate equivalence group of approximately 20 cells that consequently give rise to two distinct sub-types of muscle fibers: the superficial slow muscle fibers (SSFs) and muscle pioneer cells (MPs), distinguished by specific gene expression and cell behaviors. Using a combination of live imaging, retrospective and indicative fate mapping, and genetic studies, we show that MP and SSF precursors segregate at the beginning of segmentation and that they arise from distinct regions along the anterior-posterior (AP) and dorsal-ventral (DV) axes of the adaxial cell compartment. FGF signaling restricts MP cell fate in the anterior-most adaxial cells in each somite, while BMP signaling restricts this fate to the middle of the DV axis. Thus our results reveal that the synergistic actions of HH, FGF, and BMP signaling independently create a three-dimensional (3D) signaling milieu that coordinates cell fate within the adaxial cell equivalence group.
    PLoS Genetics 10/2012; 8(10):e1003014. DOI:10.1371/journal.pgen.1003014 · 7.53 Impact Factor
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    ABSTRACT: Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-α2 gene (LAMA2). Laminin-α2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2(cl501/cl501), exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8-15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-α2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-α2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD.
    PLoS ONE 08/2012; 7(8):e43794. DOI:10.1371/journal.pone.0043794 · 3.23 Impact Factor
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    ABSTRACT: Laminins form essential components of the basement membrane and are integral to forming and maintaining muscle integrity. Mutations in the human Laminin-alpha2 (LAMA2) gene result in the most common form of congenital muscular dystrophy, MDC1A. We have previously identified a zebrafish model of MDC1A called candyfloss (caf), carrying a loss-of-function mutation in the zebrafish lama2 gene. In the skeletal muscle, laminins connect the muscle cell to the extracellular matrix (ECM) by binding either dystroglycan or integrins at the cell membrane. Through epistasis experiments, we have established that both adhesion systems individually contribute to the maintenance of fibre adhesions and exhibit muscle detachment phenotypes. However, larval zebrafish in which both adhesion systems are simultaneously genetically inactivated possess a catastrophic failure of muscle attachment that is far greater than a simple addition of individual phenotypes would predict. We provide evidence that this is due to other crucial laminins present in addition to Lama2, which aid muscle cell attachments and integrity. We have found that lama1 is important for maintaining attachments, whereas lama4 is localized and up-regulated in damaged fibres, which appears to contribute to fibre survival. Importantly, our results show that endogenous secretion of laminins from the surrounding tissues has the potential to reinforce fibre attachments and strengthen laminin-ECM attachments. Collectively these findings provide a better understanding of the cellular pathology of MDC1A and help in designing effective therapies.
    Human Molecular Genetics 07/2012; 21(21):4718-31. DOI:10.1093/hmg/dds312 · 6.39 Impact Factor
  • Santiago Barrera Acevedo · Thomas E. Hall
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    ABSTRACT: In this paper we show the existence of perfect sequences, of unbounded lengths, over the basic quaternions {1,−1,i,−i,j,−j,k,−k}. Perfect sequences over the quaternion algebra were first introduced in 2009. One year later, a perfect sequence of length 5,354,228,880, over a quaternion alphabet with 24 elements, was shown. At this point two main questions were stated: Are there perfect sequences of unbounded lengths over the quaternion algebra? If so, is it possible to restrict the alphabet size to a small one? We answer these two questions by proving that any Lee sequence can always be converted into a sequence over the basic quaternions, which is an alphabet with 8 elements, and then by using the existence of Lee sequences of unbounded lengths to prove the existence of perfect sequences of unbounded lengths over the basic quaternions.
    Proceedings of the 7th international conference on Sequences and Their Applications; 06/2012
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    ABSTRACT: Adult zebrafish show a remarkable capacity to regenerate their spinal column after injury, an ability that stands in stark contrast to the limited repair that occurs within the mammalian CNS post-injury. The reasons for this interspecies difference in regenerative capacity remain unclear. Here we demonstrate a novel role for Fgf signaling during glial cell morphogenesis in promoting axonal regeneration after spinal cord injury. Zebrafish glia are induced by Fgf signaling, to form an elongated bipolar morphology that forms a bridge between the two sides of the resected spinal cord, over which regenerating axons actively migrate. Loss of Fgf function inhibits formation of this "glial bridge" and prevents axon regeneration. Despite the poor potential for mammalian axonal regeneration, primate astrocytes activated by Fgf signaling adopt a similar morphology to that induced in zebrafish glia. This suggests that differential Fgf regulation, rather than intrinsic cell differences, underlie the distinct responses of mammalian and zebrafish glia to injury.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2012; 32(22):7477-92. DOI:10.1523/JNEUROSCI.0758-12.2012 · 6.34 Impact Factor
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    ABSTRACT: The Hedgehog (HH) signaling pathway is a central regulator of embryonic development, controlling the pattern and proliferation of a wide variety of organs. Previous studies have implicated the secreted protein, Scube2, in HH signal transduction in the zebrafish embryo (Hollway et al., 2006; Kawakami et al., 2005; Woods and Talbot, 2005) although the nature of the molecular function of Scube2 in this process has remained undefined. This analysis has been compounded by the fact that removal of Scube2 activity in the zebrafish embryo leads to only subtle defects in HH signal transduction in vivo (Barresi et al., 2000; Hollway et al., 2006; Ochi and Westerfield, 2007; van Eeden et al., 1996; Wolff et al., 2003). Here we present the discovery of two additional scube genes in zebrafish, scube1 and scube3, and demonstrate their roles in facilitating HH signal transduction. Knocking down the function of all three scube genes simultaneously phenocopies a complete loss of HH signal transduction in the embryo, revealing that Scube signaling is essential for HH signal transduction in vivo. We further define the molecular role of scube2 in HH signaling.
    Developmental Biology 05/2012; 368(2):193-202. DOI:10.1016/j.ydbio.2012.05.007 · 3.55 Impact Factor
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    ABSTRACT: Author Summary The transition of vertebrates from water to land is a fundamental step in the evolution of terrestrial life. Innovations that were critical to this transition were the evolution of a weight bearing pelvis, hindlimbs and their associated musculature, and the development of the “rear wheel drive” strategy that predominates in terrestrial locomotion. The fossil record can reveal how the skeletal framework of the load-bearing limbs of tetrapods (animals descended from fish) has evolved, but as soft tissues are rarely preserved within the fossil record, it can shed little light on how the accompanying dramatic alterations of the limb musculature arose developmentally. To examine this question we determined the mechanisms that generate fin muscles within larvae of living species representing several clades of fish across the vertebrate phylogeny. Using this comparative approach and a novel somite transplantation technique in zebrafish, we determine that the pelvic fin muscles of bony fish are generated by a bimodal mechanism that has features of limb/fin muscle formation in tetrapods and primitive cartilaginous fish. Using these data, we propose a unifying evolutionary hypothesis on the origins of the muscle of the paired fins and limbs, and speculate that the adoption of tetrapod mode of hindlimb muscle formation was also an evolutionary innovation critical to the success of the tetrapod transition.
    PLoS Biology 10/2011; 9(10):e1001168. DOI:10.1371/journal.pbio.1001168 · 9.34 Impact Factor
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    ABSTRACT: We demonstrate the distribution of the important extracellular matrix protein laminin in a novel biomaterial consisting of a hydrogel underpinned by nanofibrillar networks. These are formed by the immobilised enzyme mediated self-assembly of fmoc-L(3) (9-fluorenylmethoxycarbonyl-tri-leucine). The peptide assembly yields nanofibrils formed of β-sheets that are locked together via π-stacking interactions. This ordering allows the localisation of the peptide sidechains on the surface, creating a hydrophobic environment. This induces the formation of bundles of these nanofibrils producing a clear hydrogel. This mechanism enables the three dimensional distribution of laminin throughout the network via supramolecular interactions. These forces favour the formation and improve the order of the network itself, as observed by spectroscopic and mechanical testing. In order to test the stability and suitability of this class of material for in vivo applications, we utilise microinjection to deliver the biomaterial under fine spatial control into a dystrophic zebrafish model organism, which lacks laminin as a result of a genetic mutation. Using confocal and transmission electron microscopy, we confirm that the biomaterial remains stable structurally, and is confined spatially to the site of injection.
    Biomaterials 08/2011; 32(22):5304-10. DOI:10.1016/j.biomaterials.2011.03.078 · 8.56 Impact Factor
  • Emily K Don · Thomas E Hall · Peter D Currie · Nicholas J Cole
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    ABSTRACT: We describe the morphology of a zebrafish strain which lacks pelvic fins but no other abnormalities. This description is the first step of analyzing hindlimb loss in an established model organism. By combining light microscopy, bone and cartilage staining, scanning electron microscopy and histological sections we were able to comprehensively describe the morphology of the developing pelvic fins of a pelvic finless zebrafish in contrast with the developing pelvic fins of wild-type zebrafish. We have shown that although adult pelvic finless zebrafish completely lack pelvic fins, they do develop mesenchymal bulges in the pelvic regions at the pelvic fin development stage. Understanding the morphology and the subsequent genetic analysis of this fish will lead to important insights into both pelvic fin/hindlimb developmental mechanisms and the evolution of hindlimb loss. It is for this reason that we present a morphological analysis of pelvic fin development and loss in this genetically tractable model species.
    Journal of Morphology 05/2011; 272(5):583-9. DOI:10.1002/jmor.10938 · 1.74 Impact Factor
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    Tamar Sztal · Silke Berger · Peter D Currie · Thomas E Hall
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    ABSTRACT: Laminins are essential components of all basement membranes and are fundamental to tissue development and homeostasis. Humans possess at least 16 different heterotrimeric laminin complexes formed through different combinations of alpha, beta, and gamma chains. Individual chains appear to exhibit unique expression patterns, leading to the notion that overlap between expression domains governs the constitution of complexes found within particular tissues. However, the spatial and temporal expression of laminin genes has not been comprehensively analyzed in any vertebrate model to date. Here, we describe the tissue-specific expression patterns of all laminin genes in the zebrafish, throughout embryonic development and into the "post-juvenile" period, which is representative of the adult body form. In addition, we present phylogenetic and microsynteny analyses, which demonstrate that the majority of our zebrafish sequences are orthologous to human laminin genes. Together, these data represent a fundamental resource for the study of vertebrate laminins.
    Developmental Dynamics 02/2011; 240(2):422-31. DOI:10.1002/dvdy.22537 · 2.38 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. As in humans, zebrafish dystrophin is initially expressed at the peripheral ends of the myofibres adjacent to the myotendinous junction and gradually shifts to non-junctional sites. Dystrophin-deficient zebrafish larvae are characterised by abundant necrotic fibres being replaced by mono-nucleated infiltrates, extensive fibrosis accompanied by inflammation, and a broader variation in muscle fibre cross-sectional areas. Muscle progenitor proliferation cannot compensate for the extensive skeletal muscle loss. Live imaging of dystrophin-deficient zebrafish larvae documents detaching myofibres elicited by muscle contraction. Correspondingly, the progressive phenotype of dystrophin-deficient zebrafish resembles many aspects of the human disease, suggesting that specific advantages of the zebrafish model system, such as the ability to undertake in vivo drug screens and real time analysis of muscle fibre loss, could be used to make novel insights relevant to understanding and treating the pathological basis of dystrophin-deficient muscular dystrophy.
    Neuromuscular Disorders 12/2010; 20(12):826-32. DOI:10.1016/j.nmd.2010.08.004 · 2.64 Impact Factor
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    ABSTRACT: The skeletal muscle basement membrane fulfils several crucial functions during development and in the mature myotome and defects in its composition underlie certain forms of muscular dystrophy. A major component of this extracellular structure is the laminin polymer, which assembles into a resilient meshwork that protects the sarcolemma during contraction. Here we describe a zebrafish mutant, softy, which displays severe embryonic muscle degeneration as a result of initial basement membrane failure. The softy phenotype is caused by a mutation in the lamb2 gene, identifying laminin beta2 as an essential component of this basement membrane. Uniquely, softy homozygotes are able to recover and survive to adulthood despite the loss of myofibre adhesion. We identify the formation of ectopic, stable basement membrane attachments as a novel means by which detached fibres are able to maintain viability. This demonstration of a muscular dystrophy model possessing innate fibre viability following muscle detachment suggests basement membrane augmentation as a therapeutic strategy to inhibit myofibre loss.
    Development 11/2009; 136(19):3367-76. DOI:10.1242/dev.034561 · 6.46 Impact Factor
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    ABSTRACT: Mutations in the human laminin alpha2 (LAMA2) gene result in the most common form of congenital muscular dystrophy (MDC1A). There are currently three models for the molecular basis of cellular pathology in MDC1A: (i) lack of LAMA2 leads to sarcolemmal weakness and failure, followed by cellular necrosis, as is the case in Duchenne muscular dystrophy (DMD); (ii) loss of LAMA2-mediated signaling during the development and maintenance of muscle tissue results in myoblast proliferation and fusion defects; (iii) loss of LAMA2 from the basement membrane of the Schwann cells surrounding the peripheral nerves results in a lack of motor stimulation, leading to effective denervation atrophy. Here we show that the degenerative muscle phenotype in the zebrafish dystrophic mutant, candyfloss (caf) results from mutations in the laminin alpha2 (lama2) gene. In vivo time-lapse analysis of mechanically loaded fibers and membrane permeability assays suggest that, unlike DMD, fiber detachment is not initially associated with sarcolemmal rupture. Early muscle formation and myoblast fusion are normal, indicating that any deficiency in early Lama2 signaling does not lead to muscle pathology. In addition, innervation by the primary motor neurons is unaffected, and fiber detachment stems from muscle contraction, demonstrating that muscle atrophy through lack of motor neuron activity does not contribute to pathology in this system. Using these and other analyses, we present a model of lama2 function where fiber detachment external to the sarcolemma is mechanically induced, and retracted fibers with uncompromised membranes undergo subsequent apoptosis.
    Proceedings of the National Academy of Sciences 05/2007; 104(17):7092-7. DOI:10.1073/pnas.0700942104 · 9.67 Impact Factor

Publication Stats

594 Citations
166.71 Total Impact Points


  • 2014–2015
    • University of Queensland
      • Institute for Molecular Bioscience
      Brisbane, Queensland, Australia
  • 2011–2014
    • University of Vic
      Vic, Catalonia, Spain
  • 2010–2014
    • Monash University (Australia)
      • Australian Regenerative Medicine Institute
      Melbourne, Victoria, Australia
  • 2007–2011
    • Victor Chang Cardiac Research Institute
      דרלינגהרסט, New South Wales, Australia
  • 2003–2004
    • University of St Andrews
      • School of Biology
      Saint Andrews, Scotland, United Kingdom
    • University of Dundee
      • Division of Cell and Developmental Biology
      Dundee, Scotland, United Kingdom